Mammalian cells utilize signaling pathways to regulate various processes, especially cell growth and cell cycling. For example, the mitogen-activated protein kinase (MAPK) pathway (also known as Raf-MEK-ERK phosphorylation cascade) transfers signals from growth factors and hormones binding at cell surface receptors to transcription factors in the nucleus to control gene expression and other cellular functions [Seeger, R. et al., FASEB J. 1995, 9, 726; Cobb, M. H. et al., J Biol. Chem. 1995, 270, 14843; Schaeffer, H. J. et al., Mol. Cell. Biol. 1999, 19, 2435; Garrington, T. P. et al., Curr. Opin Cell. Biol. 1999, 11, 211]. Aberrant signal transduction via signaling pathways that are responsible for the regulation of cell growth and division has been shown to cause uncontrolled cell growth or cancer.
It is known that MAPK kinases (MEK) are important components in the MAPK pathway for regulating diverse cellular events, including cell transformation, proliferation, differentiation, and/or apoptosis. MEK and ERK (extracellular signal regulated protein kinase, or MAP kinase) are frequently dysregulated in human cancers [Oka, H. et al., Cancer Res. 1995, 55, 4182; Sivaraman, V. S. et al., J. Clin. Invest. 1997, 99, 1478; Hoshino, R. et al., Oncogene 1999, 18, 813] and have been recognized as potential drug targets for therapeutic intervention in the treatment of cancer, inflammation, leukemia, and other diseases [Stein, B. et al., Annu. Rep. Med. Chem. 1996, 31, 289; Sedlacek, H. H. Drugs 2000, 59, 435; Levitt, M. L. et al., Invest. New Drugs 1999, 17, 213; Cohen, P., Curr. Opin. Chem. Biol. 1999, 3, 459; Levitzki, A. Pharmacol., Ther. 1999, 82, 231]. In other examples, constitutively active MEK mutants are known to induce cell transformation and produce tumors in nude mice [Brunet, A. et al., Oncogene 1994, 9, 3379; Cowley, S. at el., J. Cell 1994, 77, 841; Mansour, S. J. et al., Science 1994, 265, 966]. In still further examples, over-expression and/or over-activation of MEK (or its substrate ERK) protein have also been found to be associated with various human cancers, including kidney, breast, colon, and oral carcinomas, leukemia, and glial neoplasmas [Oka, H. et al., Cancer Res. 1995, 55, 4182; Sivaraman, V. S. et al., J. Clin. Invest. 1997, 99, 1478; Kono, Y. et al., Jpn. J. Cancer Res. 1998, 89, 903; Towatari, M. et al., Leukemia 1997, 11, 479; Mandell, J. W. et al., Am. J Pathol. 1998, 153, 1411].
Thus, it is believed that inhibitors of the MAPK pathway, and especially inhibitors of MEK and/or ERK may serve as selective inhibitors of the growth of mammalian cancer cells. There are numerous such inhibitors known in the art, and exemplary classes of inhibitors are described in U.S. Pat. Nos. 6,440,966 and 6,506,798 to Barrett et al. Here, the inventors employ selected benzenesulfonamide derivatives, and various 4-arylamino, 4-aryloxy, and 4-arylthio diarylamines, respectively, as MEK inhibitors. Larson and Gant describe in U.S. Pat. Nos. 6,235,764, 6,548,526, and 6,380,214, respectively, various isothiazole compounds which exhibit some similarity in structure to Barrett's compounds. However, the inventors report biological activity only on neovascularisation, but not on MEK/ERK inhibition. Further known isothiazole compounds include those described by Shishoo et al. (Journal of Heterocyclic Chemistry 1988, 25(3): 759–65) and U.S. Pat. No. 3,230,229 to Hatchard, but none of these references teaches kinase inhibition using such compounds. In still another example, Boschelli et al. describe, in U.S. Pat. No. 6,521,618, various 3-cyanoquinolines, 3-cyano-1,6-naphthyridines and 3-cyano-1,7-naphthyridines as selective MEK inhibitors.
While certain isothiazole compounds are known to exhibit kinase inhibitory effects, selectivity towards MEK and/or ERK and specificity to inhibit malignant cells remains often problematic. Furthermore, toxicity of such known MEK or ERK inhibitors is often encountered, especially at higher concentrations. Thus, there is still a need to provide improved compositions and methods of inhibiting protein kinases, and especially MEK and/or ERK.